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by Nat Jones, RPh, FAPC, PCCA Clinical Compounding Pharmacist, and Fabiana Banov, RPh, MS, PCCA Senior Formulation Pharmacist
Minoxidil is the number one ingredient used in topical hair restoration formulas worldwide since hypertrichosis was discovered as an adverse event when minoxidil was used to treat hypertension. It is the only topical active pharmaceutical ingredient (API) that is FDA approved for androgenic alopecia in both men and women.
Minoxidil is a pro-drug requiring bioactivation into minoxidil sulfate. The enzyme that catalyzes this reaction in the hair follicle is minoxidil sulfotransferase (SULT1A1).1 Due to the prolonged duration of therapy required (approximately 6 months) for an effective response, expression of SULT1A1 as a biomarker for predicting treatment response can be an important predictive clinical tool. Studies show that sulfation is a critical step for the hair-growth effects of minoxidil and that the sulfated metabolite directly affects hair follicles.
Assays of SULT1A1 activity indicated that vibrissae follicles metabolize minoxidil to minoxidil sulfate. Dose-response studies showed that minoxidil sulfate is 14 times more potent than minoxidil in stimulating cysteine incorporation in cultured follicles.2 Variations between individuals in sulfotransferase activity may be the cause of the discrepancy in minoxidil efficiency.3
Minoxidil shortens the telogen phase, causing the follicles to prematurely enter the anagen phase, which may induce telogen effluvium after the initiation of therapy. It also extends the duration of the anagen phase and increases both hair length and diameter. This effect takes about eight weeks to occur and maximizes after four months.
Minoxidil appears to act on the potassium channels of vascular smooth muscles and hair follicles, which may induce the following effects:
Induction of vascular endothelial growth factor (VEGF) expression, which increases vascularization around the hair follicles and contributes to hair growth.
Activation of the prostaglandin-endoperoxide synthase, one of which stimulates hair growth.
Inhibition of androgen, which affects the androgen-sensitive hair follicles.
Direct stimulation of the hair follicles: minoxidil may act as an “epidermal growth factor” on matrix cells and delay their aging, thus prolonging the duration of the anagen phase via the activation of the beta-catenin pathway.4
In a study conducted on 435 people using oral minoxidil, 2% experienced postural hypotension and 8% had general symptoms of lightheadedness. Of those experiencing lightheadedness, 11% needed to stop treatment. Although the study authors concluded oral minoxidil is effective at stimulating hair growth, adverse events occurred: 93% experienced hypertrichosis, 10% experienced pedal edema and 10% experienced ECG alteration. The authors also noted these adverse events were not seen in people using topical minoxidil in previous studies.5
Androgenic alopecia (AA) is one of the most common chronic problems seen by dermatologists. When treating AA in men or women, suppression of the 5α-reductase-driven conversion of testosterone to dihydrotestosterone (DHT) is essential in controlling the stimulation of the hair loss. As such, the addition of a 5α-reductase inhibitor to formulas is necessary for long-term treatment success.
For this reason, additional APIs used in combination with minoxidil in compounded formulas include finasteride, dutasteride, azelaic acid, progesterone (the body’s own natural 5α-reductase inhibitor), tretinoin, latanoprost, clobetasol propionate, melatonin and others, with finasteride used most often. Finasteride has shown synergism with minoxidil, resulting in significant increase in hair counts when combined with topical minoxidil, with maintenance of good hair density in combination with topical 5% minoxidil.6,7
Tretinoin is another valuable API for these formulations because it enhances sulfotransferase activity. It is also known as a keratolytic and is believed to enhance minoxidil penetration.8
Minoxidil may appear as a challenging API when compounding preparations. The API is prone to crystallization, insolubility, pH instability, precipitation and more. As such, it is important to use the correct PCCA formula and PCCA ingredient, or combination of PCCA ingredients, to ensure a more stable preparation.
A version of this article originally appeared entirely in PCCA’s members-only magazine, the Apothagram.
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